Search

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

Purpose: Trabeculectomy surgery is a commonly performed procedure for treatment of glaucoma. While the goal is to lower intraocular pressure, over-filtration may cause hypotony with ocular structural changes and vision loss. Observations: A 53-year-old woman with primary open-angle glaucoma was referred to our service for further evaluation. The patient previously underwent trabeculectomy 9 years prior and was found to have a cataract and hypotony maculopathy in the right eye. Treatment options included cataract surgery alone, bleb revision alone, or combined cataract extraction and bleb revision. Biometry revealed corneal astigmatism in the right eye, and significant disparity in axial length between the two eyes. Since the axial length and corneal astigmatic changes were presumed to be at least partially reversible, measurements from the non-operative left eye influenced the lens selection for the hypotonous right eye. The patient underwent combined phacoemulsification and bleb revision. While IOP increased and hypotony was partly reversed, there was hyperopic and astigmatic refractive surprise after surgery.The patient subsequently underwent intraocular lens exchange using biometric values of the previously hypotonous eye and met the target post-operative refractive goal. Conclusions and importance: This case demonstrates changes to the axial length and ocular structure following longstanding hypotony maculopathy may be permanent, even after restoration of normotensive intraocular pressure.

Bacteria that cause infectious diseases adopt biofilms as one of their most prevalent lifestyles. Biofilms enable bacteria to tolerate environmental stress and evade antibacterial agents. This bacterial defense mechanism has rendered the use of antibiotics ineffective for the treatment of infectious diseases. However, many highly drug-resistant microbes have rapidly emerged owing to such treatments. Different signaling mechanisms regulate bacterial biofilm formation, including cyclic dinucleotide (c-di-GMP), small non-coding RNAs, and quorum sensing (QS). A cell density-dependent phenomenon, QS is associated with c-di-GMP (a global messenger), which regulates gene expression related to adhesion, extracellular matrix production, the transition from the planktonic to biofilm stage, stability, pathogenicity, virulence, and acquisition of nutrients. The article aims to provide information on inhibiting biofilm formation and disintegrating mature/preformed biofilms. This treatment enables antimicrobials to target the free-living/exposed bacterial cells at lower concentrations than those needed to treat bacteria within the biofilm. Therefore, a complementary action of antibiofilm and antimicrobial agents can be a robust strategic approach to dealing with infectious diseases. Taken together, these molecules have broad implications for human health.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Purpose: To develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography. Design: Cross-sectional study. Participants: Forty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK. Methods: Scheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT. Main Outcome Measures: Predictive power (R2) and mean difference between predicted and observed change in CCT. Results: The gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R2 = 0.80; 95% confidence interval [CI], 0.71–0.89) and the mean difference between predicted and observed change was, by definition, 0 μm. When the same 5 parameters were fit to the validation group, the model performed very highly (R2 = 0.89; 95% CI, 0.84–0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R2 = 0.78; 95% CI, 0.68–0.88), and the mean difference was 4 μm (predicted minus observed). Conclusions: Scheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

Abstract: Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Objective: Sleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-). Methods: Using data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared. Results: In the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P

Background: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. Methods: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses. Findings: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT). Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

Hispanics/Latinos face specific sociocultural stressors associated with their marginalized status in the United States. While stress is known to cause poor sleep, the differential effects of the specific stressors faced by Hispanics/Latinos have not been evaluated. Using cross-sectional data from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study, we conducted weighted generalized linear models to evaluate the associations of acculturation stress, ethnic discrimination, and chronic moderate/severe stress with self-reported sleep outcomes (insomnia symptoms, daytime sleepiness, sleep duration) in individual and aggregate models adjusted for site, socio-demographics, behavioral, and medical conditions. Participants included 5313 Hispanic/Latino adults; 43.5% ≥ age 45, 54.8% female, and 22.0% US-born. Chronic moderate/severe stress, ethnic discrimination, and acculturation stress were each positively associated with sleep. In the adjusted aggregate model, only chronic moderate/severe stress was associated with insomnia symptoms (exp(b) = 1.07 for each additional stressor, 95% CI = 1.05, 1.09). Both acculturation stress (exp(b) = 1.05 for each additional SD, 95% CI = 1.02, 1.10) and ethnic discrimination (exp(b) = 1.05 for each additional SD, 95% CI = 1.01, 1.08) were associated with daytime sleepiness. Each SD increase in ethnic discrimination related to a 16% and 13% increased prevalence of short (< 7 h) (RRR = 1.16, 95% CI = 1.02, 1.31) and long sleep duration (> 9 h) (RRR = 1.13, 95% CI = 1.00, 1.27), respectively. These associations were consistent across sex. Acculturation stress and ethnic discrimination are associated with poor sleep in Hispanics/Latinos. Future research should explore whether behavioral sleep interventions minimize the impact of sociocultural stressors on sleep.

Abstract: Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.

Objective: To assess the safety and immunogenicity of the MF59-adjuvanted seasonal trivalent inactivated influenza vaccine (aIIV3; Fluad) in children aged 6 months through 5 years who are at risk of influenza complications. Methods: A retrospective analysis was performed to examine unsolicited adverse events (AEs) in an integrated dataset from six randomized clinical studies that compared aIIV3 with non-adjuvanted inactivated influenza vaccines (IIV3). The integrated safety set comprised 10 784 children, of whom 373 (3%) were at risk of influenza complications. Results: The at-risk safety population comprised 373 children aged 6 months through 5 years: 179 received aIIV3 and 194 received non-adjuvanted IIV3 (128 subjects received a licensed IIV3). The most important risk factors were respiratory system illnesses (62–70%) and infectious and parasitic diseases (33–39%). During the treatment period, unsolicited AEs occurred in 54% of at-risk children and 55% of healthy children who received aIIV3; of those receiving licensed IIV3, 59% of at-risk and 62% of healthy subjects reported an unsolicited AE. The most common AEs were infections, including upper respiratory tract infection. Serious AEs (SAEs) were reported in

Objective: To demonstrate the potential of an MF59-adjuvanted inactivated trivalent seasonal influenza vaccine (aIIV3; Fluad™) to improve the immune response in young children, we review the immunogenicity, efficacy, and safety/tolerability of aIIV3 from a comprehensive clinical development program in a pediatric population with a specific need for improved influenza vaccines. Methods: Data were analyzed from a series of 1 phase Ib, 3 phase II, and 2 phase III studies involving 11,942 children aged 6 months through 5 years. Results: The clinical data showed that aIIV3 had statistically significantly greater immunogenicity and efficacy in the prevention of influenza compared to conventional inactivated trivalent seasonal influenza vaccines (IIV3s). The safety profile of aIIV3 was generally similar to that of nonadjuvanted IIV3, apart from an increased frequency of solicited adverse events (AEs) following vaccination. The majority of solicited AEs were mild or moderate in severity and resolved within 1 to 3 days. Conclusions: aIIV3 was well tolerated, with immunogenicity and efficacy exceeding that of conventional IIV3 in children 6 months through 5 years of age. The MF59-adjuvanted vaccine has the potential to fulfill an unmet clinical need in the prevention of seasonal influenza in this age group. Keywords: Children, Influenza, Vaccine, Adjuvant, MF59

Purpose: Describe a case of intraocular plasmacytoma in a patient with multiple myeloma successfully treated with photon irradiation. Observations: A 61-year-old man with a history of relapsing/refractory multiple myeloma and left frontal bone plasmacytoma treated with monthly belantamab mafodotin salvage chemotherapy developed bilateral treatment-related corneal keratopathy. An iris mass was incidentally noted in the right eye during a follow-up examination. The mass was amelanotic with diffuse intrinsic vasculature involving the pupillary margin from 1:30 to 10:30. Fundus examination showed an irregularly shaped amelanotic superotemporal scleral lesion in the right eye and two smaller amelanotic scleral lesions in the left eye. Given known systemic multiple myeloma and history of left frontal bone plasmacytoma, a presumed diagnosis of iris and scleral plasmacytoma was made. Due to rapid progression of the iris plasmacytoma despite systemic chemotherapy, the patient was treated with 20 Gy photon irradiation to the anterior and posterior segments of both eyes. One month after photon irradiation, there was complete regression of the iris plasmacytoma, and the scleral lesions in both eyes also appeared to be regressing despite systemic progression of multiple myeloma. Conclusions and importance: Intraocular plasmacytoma is rare and can occur in isolation but typically occurs as a manifestation of systemic multiple myeloma. Intraocular plasmacytoma can be successfully treated with photon irradiation in patients with multiple myeloma who progress on systemic chemotherapy.

Purpose: To report a case of recurrent iris post-transplant lymphoproliferative disorder (PTLD) treated with ultra-low-dose (boom-boom) radiotherapy (RT). Observations: A 12-year-old Caucasian male with a history of bilateral, recurrent iris PTLD of the extranodal marginal zone lymphoma (MALT) type presented with persistent bilateral anterior chamber cellular infiltration, which was incompletely controlled on topical corticosteroids, and with elevated intraocular pressure (IOP) in the right eye secondary to steroid response. The patient was diagnosed with PTLD recurrence and was successfully treated with ultra-low-dose RT to both eyes in 2 fractions of 2 Gy. At 15 month follow-up the patient maintained complete disease control with normal IOP off all topical ophthalmic medications. Conclusions and Importance: Ultra-low-dose RT for ocular PTLD of the MALT subtype represents a novel therapeutic approach that may provide a durable treatment response and could be considered as either primary or adjuvant therapy for this rare condition.